Esters and amides derivatives of α-(phenoxy)phenylacetic acids, such as halofenate, are chiral compounds and are useful in ameliorating a variety of physiological conditions, including conditions associated with blood lipid deposition, e.g., Type II diabetes and hyperlipidema. See, for example, U.S. Pat. Nos. 3,517,050 and 6,262,118. α-(phenoxy)phenylacetic acids contain a single chiral center at an asymmetrically substituted carbon atom alpha to the carbonyl carbon atom, and therefore exist in two enantiomeric forms.
Cytochrome P450 2C9 is an enzyme known to play a significant role in the metabolism of specific drugs. It is known to one skilled in the art that changes in drug metabolism mediated by inhibition of cytochrome P450 enzymes has a high potential to precipitate significant adverse effects in patients. It is also known that a racemic α-(phenoxy)phenylacetic acid, e.g., halofenic acid, inhibits cytochrome P450 2C9. See, for example, U.S. Pat. No. 6,262,118. Thus, administration of a racemic α-(phenoxy)phenyl-acetic acid, such as halofenic acid or its derivatives, can lead to a variety of drug interaction problems with other drugs, including anticoagulants, anti-inflammatory agents and other drugs that are metabolized by this enzyme. It has been found that the (−)-enantiomer of halofenic acid is about twenty-fold less active in its ability to inhibit cytochrome P450 2C9 compared to the (+)-enantiomer. Id. Thus, it is desirable to administer the (−)-enantiomer of halofenic acid or its derivatives which is substantially free of the (+)-enantiomer to reduce the possibility of drug interactions.
Therefore, there is a need for an efficient process for producing a product enriched in a desired enantiomer of a α-(phenoxy)phenylacidic acid, e.g., (−)-halofenic acid.